Protein kinase mediators of integrin signal transduction

 Protein kinases are important mediators of signal transduction initiated by soluble growth factors and cytokines. Cellular interactions with the extracellular matrix are mediated largely by members of the integrin class of cell adhesion molecules, which also subsume signal transduction functions required for cell growth, differentiation, and survival. Here we review the involvement of protein kinases in mediating integrin intracellular signal transduction and the possible role for these molecules in regulating integrin adhesion. Although in most cases mechanistic details are incomplete, the emerging theme of protein kinases mediating cross-talk between growth factor receptor and integrin signalling systems provides a timely backdrop against which to present new developments in this area. The contribution of the actin cytoskeleton to integrin signal transduction is discussed, with respect to the concept of ’solid-state’ signalling providing a mechanism for imposing order on the protein-protein interactions which underlie signal discrimination. Moreover, we review evidence that dysregulated integrin signalling contributes to pathological processes including arthritis, thrombasthenia, leucocyte adhesion deficiencies, and tumour angiogenesis and invasion. Received: 14 May 1996 / Accepted: 2 July 1996     

Deletion of integrin-linked kinase from skeletal muscles of mice resembles muscular dystrophy due to alpha 7 beta 1-integrin deficiency

Integrin-linked kinase (Ilk) is a serine/threonine kinase and an adaptor protein that links integrins to the actin cytoskeleton and to a number of signaling pathways involved in integrin action. We hypothesized that Ilk may act as an important effector of integrins in skeletal muscle, where these receptors provide a critical link between the sarcolemma and the extracellular matrix. Using the cre/lox system, we deleted Ilk from skeletal muscles of mice. The resulting mutants developed a progressive muscular dystrophy with multiple degenerating and regenerating muscle fibers, increased central nuclei, and endomysial fibrosis. These defects were widespread but were most severe near myofascial junctions where Ilk mutants showed displacement of focal adhesion-related proteins, including vinculin, paxillin, focal adhesion kinase, dystrophin, and the alpha 7 beta 1D-integrin subunits. Distal ends of mutant muscle fibers appeared irregular, and there was restructuring of the actin cytoskeleton. These findings resemble those seen in humans and mice lacking the alpha 7-integrin subunit and suggest that Ilk may act as a cytoplasmic effector of alpha 7 beta1-integrin in the pathogenesis of these deficiencies.     

A case of pulmonary sarcoidosis, not tuberculosis

The case of sarcoidosis of the lungs is described in a 50 years old female who presented with symptoms similar to pulmonary tuberculosis. As she showed no improvement on anti-tubercular therapy, sarcoidosis was suspected and confirmed by endobronchial biopsy and she responded well to treatment.     

The tumor invasion inhibitor dihydromotuporamine C activates RHO, remodels stress fibers and focal adhesions, and stimulates sodium-proton exchange

The motuporamines are macrocyclic alkaloids that inhibit tumor cell invasion by an, as yet, unknown mechanism. A structure-activity study recently identified dihydromotuporamine C (dhMotC) as a highly active and readily synthesized analogue. Here, we show that dhMotC causes subtle cytoskeletal alterations in highly invasive MDA231 breast tumor cells that include an increase in the thickness and number of cytoplasmic actin stress fibers. Experiments with serum-starved Swiss 3T3 fibroblasts showed that micromolar concentrations of dhMotC that inhibit tumor cell invasion induce the formation of new stress fibers and large focal adhesion complexes that are dispersed around the entire cell periphery. dhMotC treatment of Swiss 3T3 cells also initiates a strong, long-lived activation of the small GTP-binding protein Rho, and it stimulates Rho kinase-dependent sodium-proton exchanger activity. Liposome-mediated cell loading of C3 exoenzyme prevents dhMotC-mediated Rho activation and stress fiber formation in 3T3 cells. C3 exoenzyme loading also reestablishes elongated MDA231 breast tumor cell invasion in the presence of dhMotC. Taken together, these results indicate that the ability to activate Rho is one important determinant of the anti-invasive activity of dhMotC.     

The role of integrin-linked kinase (ILK) in cancer progression

Integrin-linked kinase (ILK) is an intracellular protein, which interacts with the cytoplasmic domains of integrin beta1 and beta3 subunits. ILK is a 59kDa protein containing a phosphoinositide phospholipid-binding domain flanked by an N-terminal ankyrin repeat domain and a C-terminal serine/threonine protein kinase domain. Genetic and biochemical evidence have established an essential role of ILK in connecting integrins to the actin cytoskeleton. Apart from integrins, ILK interacts with several adaptor and signaling proteins resulting in its activation and localization to focal adhesion plaques. The kinase activity of ILK is stimulated upon integrin engagement, as well as by growth factors and chemokines in a PI-3Kinase-dependent manner. ILK can mediate the phosphorylation of a variety of intracellular substrates, most notable of which are: protein kinase B (PKB/Akt), glycogen synthase kinase-3 (GSK-3) and myosin light chain. Gain and loss of function strategies have shown that overexpression, and/or constitutive activation of ILK results in oncogenic transformation and progression to invasive and metastatic phenotypes. In addition ILK expression and activity are upregulated in several types of cancers. In this review, we summarize the adaptor and signaling properties of ILK, and also progress in the identification of therapeutic strategies for inhibition of ILK activity.     

Prevalence of abnormal gastric emptying in asymptomatic women with newly detected diabetes and its reversibility after glycemic control—A prospective case control study

ObjectiveEffects of systemic hyperglycemia and normoglycemia on gastric emptying in people with type 2 diabetes are not clear. The aim of the study was to investigate the gastric emptying time in people with newly detected diabetes before and after control of diabetes compared with healthy controls.MethodsGastric emptying to solid meal was studied in 30 asymptomatic women with newly detected diabetes before and after achieving euglycemia and compared with 20 healthy age, sex and weight matched controls using egg white labelled with Technetium 99 m Sulfur Colloid.ResultsDelayed gastric emptying was seen in 90% of women with diabetes and none in healthy controls. Lag phase was 83.1 ± 11.8 min in cases compared to 37.2 ± 4.0 in controls (p = 0.05). Gastric emptying at 4 h was 46.73% ± 4.84% in cases and 97.65% ± 0.59% in controls (p = 0.05).T50 was 250 ± 8.8 min in cases against 94.70 ± 5.10 min in controls (p < 0.05). After control of diabetes, lag phase normalized to 37.2 ± 4.0 min against 35.2 ± 4.6 min in controls. Similarly all other parameters also normalized after control of diabetes.ConclusionsDelayed gastric emptying to solids was seen in 90% of women with type 2 diabetes at the time of hyperglycemia and normalized after control of diabetes.